CN107550852B - Solvent for temsirolimus injection and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and provides a temsirolimus injection solvent which mainly comprises a solubilizer, L-arginine, methylparaben and water for injection. Weighing a prescription amount of solubilizer and methyl paraben, adding the solubilizer and the methyl paraben into a proper amount of water for injection, stirring for dissolving, weighing a prescription amount of L-arginine, adding the L-arginine into the solution, metering the volume to the full volume with the water for injection, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product. The injection solvent has low organic solvent content, and avoids the inconvenience in production caused by viscosity due to overhigh organic solvent content.

Description

Solvent for temsirolimus injection and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a temsirolimus injection solvent and a preparation method thereof.

Background

Temsirolimus, also called temsirolimus, trade name: torsiel (temsirolimus, CCI-779) is a rapamycin C42 propionate derivative developed by Wyeth corporation and approved for marketing by the FDA in 5 Messaging U.S. in 2007, and temsirolimus injection was used to treat advanced renal cell carcinoma and was designated as an orphan drug, the first antineoplastic mTOR inhibitor.

Temsirolimus is 42-bis-hydroxymethyl propionate of rapamycin, exhibits cytostatic properties in vivo, and can delay the time to tumor cell development or the time to tumor recurrence. Temsirolimus binds to the cellular protein FKBP and forms a complex that inhibits the enzyme mTOR (mammalian target of rapamycin), inhibition of mTOR' S kinase activity, inhibition of various signal transduction pathways, including cytokine-activated cell proliferation, transcription of mRNAs, which regulate some key proteins in the G1 phase of the cell cycle, and IL-2-induced transcription, thereby inhibiting progression of the cell cycle from G1 to S, resulting in anticancer effects.

Wyeth company developed and filed a patent for temsirolimus injection, and its patent application publication No. CN1671385A discloses a preparation method of temsirolimus injection, which consists of a concentrated solution and a diluent, wherein the concentrated solution contains main drugs of temsirolimus, propylene glycol, ethanol, DL-alpha-tocopherol and anhydrous citric acid, and the diluent contains Tween 80, ethanol and polyethylene glycol 400.

Chinese patent application publication No. CN103099806A discloses temsirolimus for injection and a preparation method thereof, the temsirolimus for injection comprises a freeze-dried composition and a diluent, wherein the freeze-dried composition contains main drugs of temsirolimus, a dispersant, an antioxidant, anhydrous ethanol as the diluent and water for injection, the content of water in the preparation is reduced by utilizing a freeze-drying method, and the problem that the isomer of temsirolimus is enlarged during the long-term storage of the preparation is effectively avoided.

Chinese patent application publication No. CN103989676A discloses an injectable temsirolimus composition, which consists of a concentrated solution and a diluent, wherein the concentrated solution contains main drugs of temsirolimus, absolute ethyl alcohol, organic acid, propylene glycol and the like, and the diluent contains Tween 80, ethanol and polyethylene glycol 400, so that the problem that the isomer of temsirolimus is enlarged in the long-term storage process due to the introduction of water in the injection is effectively solved.

However, the inventor finds that in clinical use, the temsirolimus concentrated solution is prepared by dissolving and uniformly mixing the injection solution with a solvent for incidental injection to prepare a pre-injection solution, and then injecting the pre-injection solution into 250ml of 0.9% sodium chloride injection to prepare a solution containing about 0.1mg of temsirolimus per 1ml, and the temsirolimus isomers are very easily degraded in water, so that the variation of the temsirolimus isomers is large.

Disclosure of Invention

In order to solve the problems, the invention provides a solvent for temsirolimus injection, which comprises the following components in percentage by weight: mainly comprises solubilizer, L-arginine, methyl paraben and water for injection.

The solvent for injection of temsirolimus injection is characterized in that the solubilizer is selected from one or more of Tween 80, Tween 20, Tween 40, span 80, span 60 and polyvinylpyrrolidone, and is preferably Tween 80.

The mass-volume concentration range of the solubilizer of the solvent for injection of temsirolimus injection is 7.5-12.5%, and the preferable concentration range is 10%.

The solvent for injection of temsirolimus injection has the mass-volume concentration range of L-arginine of 1.0-1.6%, preferably 1.4%.

The injection solvent of the temsirolimus injection has the mass-volume concentration range of the methylparaben of 5-10 percent, and the preferred concentration range is 7.5 percent.

The invention further provides a preparation method of the temsirolimus injection solvent, which comprises the following steps:

weighing a prescription amount of solubilizer and methyl paraben, adding the solubilizer and the methyl paraben into a proper amount of water for injection, stirring for dissolving, weighing a prescription amount of L-arginine, adding the L-arginine into the solution, metering the volume to the full volume with the water for injection, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Compared with the prior art, the solvent for injection of temsirolimus injection of the invention comprises the following components:

1. the method can obviously inhibit the trend that the isomer of the temsirolimus in the final liquid medicine prepared by the clinical application of the temsirolimus injection is increased, and provides a product with better curative effect for clinic.

2. The injection solvent has low organic solvent content, and avoids the inconvenience in production caused by viscosity due to overhigh organic solvent content.

Detailed Description

The following examples further illustrate the preparation and advantageous effects of the present invention, and the examples are for illustrative purposes only and do not limit the scope of the present invention, and the changes and modifications apparent to those skilled in the art according to the present invention are also included in the scope of the present invention.

Example 1:

weighing 150.0g of Tween 80 and 100.0g of methyl paraben, adding into 1000.0ml of water for injection, stirring for dissolving, weighing 20.0g of L-arginine, adding into the solution, adding water for injection to a constant volume of 2000ml, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Example 2:

weighing 200.0g of Tween 80 and 150.0g of methyl paraben, adding into 1000.0ml of water for injection, stirring for dissolving, weighing 28.0g of L-arginine, adding into the solution, metering to the total volume of 2000ml with water for injection, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Example 3:

weighing 250.0g of Tween 80 and 200.0g of methyl paraben, adding into 1000.0ml of water for injection, stirring for dissolving, weighing 32.0g of L-arginine, adding into the solution, metering to the total volume of 2000ml with water for injection, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Example 4:

weighing 150.0g of span 80 and 200.0g of methyl paraben, adding into 1000.0ml of water for injection, stirring for dissolving, weighing 28.0g of L-arginine, adding into the solution, metering volume to 2000ml with water for injection, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Example 5:

weighing 150.0g of Tween 80 and 100.0g of methyl paraben, adding into 1000.0ml of water for injection, stirring for dissolving, weighing 32.0g of L-arginine, adding into the solution, adding water for injection to a constant volume of 2000ml, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Example 6:

weighing 250.0g of Tween 80 and 200.0g of methyl paraben, adding into 1000.0ml of water for injection, stirring for dissolving, weighing 20.0g of L-arginine, adding into the solution, adding water for injection to a constant volume of 2000ml, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Example 7:

weighing 250.0g of Tween 80 and 100.0g of methyl hydroxybenzoate, adding into 1000.0ml of water for injection, stirring for dissolving, weighing 20.0g of L-arginine, adding into the above solution, adding water for injection to a constant volume of 2000ml, and stirring; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Comparative example 1:

1. preparation of concentrated solutions for injection

Adding 25.0mg of anhydrous citric acid into 300.0ml of anhydrous ethanol, and stirring to dissolve; adding 25.0g of temsirolimus, 503.0g of propylene glycol and 0.75g of DL-alpha-tocopherol into the obtained solution, and stirring to dissolve; adding anhydrous ethanol under stirring to a constant volume of 1000ml, stirring, filtering, bottling, visually inspecting, and packaging to obtain the final product.

2. Preparation of solvent for injection

Weighing the tween 80720.0 g and the polyethylene glycol 400770.4 g according to the prescription amount, fixing the volume to 1800ml by using absolute ethyl alcohol, and uniformly stirring; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Comparative example 2:

1. preparation of temsirolimus freeze-dried composition for injection

Dissolving 25.0g of temsirolimus in a proper amount of absolute ethanol, stirring to dissolve the temsirolimus, adding 2.0g of ascorbic acid, shaking uniformly, adding 1000.0g of Tween 80, mixing uniformly, removing ethanol by a freeze dryer, subpackaging in penicillin bottles, and pressing and capping to obtain the temsirolimus injection.

2. Preparation of solvent for injection

Weighing 150.0g of absolute ethyl alcohol, adding 1000mL of water for injection to dilute, filtering, filling, inspecting by eyes, and packaging to obtain a finished product.

Comparative example 3:

1. preparation of concentrated solutions for injection

Adding 1.0g of L-tartaric acid and 100.0mg of S-lactic acid into 400.0g of absolute ethyl alcohol, and stirring to dissolve; adding 25.0g of temsirolimus into the obtained solution, and stirring to dissolve; slowly adding propylene glycol under stirring to 1000ml, stirring, filtering, bottling, visually inspecting, and packaging to obtain the final product.

2. Preparation of solvent for injection

Mixing tween 80400.0 g and anhydrous ethanol 200.0g, adding polyethylene glycol 400 under stirring to volume of 1000ml, stirring, filtering, bottling, inspecting, and packaging to obtain the final product.

Comparative example 4:

weighing 200.0g of Tween 80 and 150.0g of methylparaben, diluting to total volume of 2000.0ml with water for injection, and stirring for dissolving; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Comparative example 5:

weighing 28.0g of L-arginine and 150.0g of methyl hydroxybenzoate in the prescription amount, adding into 1000.0ml of water for injection, stirring uniformly, fixing the volume to 2000ml with the water for injection, and stirring until the methyl hydroxybenzoate is not completely dissolved; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Comparative example 6:

weighing 200.0g of Tween 80 and 28.0g of L-arginine, metering the volume to 2000ml by using water for injection, and stirring for dissolving; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Comparative example 7:

weighing 300.0g of Tween 80 and 250.0g of methyl paraben, adding into 1000.0ml of water for injection, stirring for dissolving, weighing 40.0g of L-arginine, adding into the solution, metering to the total volume of 2000ml with water for injection, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.

Verification examples

1 of the temsirolimus injection (25 mg/unit) was dissolved and mixed with an injection solvent in the manner shown in the following table to prepare a pre-injection solution, which was then injected into 250ml of 0.9% sodium chloride injection to prepare a solution containing about 0.1mg of temsirolimus per 1ml as a clinical solution.

Tacrolimus injection and solvent for injection examples 1-7 and comparative examples 1-7 compatibility table

Remarking: the effects of examples 1 to 7 are the same as those of example 1, and only example 1 is shown because of the large amount of data.

+ the preparation is compatible with the solvent for injection in the examples

The formulation is compatible with the injectable solvents of the examples in the absence of

Comparative example 5 methyl paraben not dissolved at all

And (3) placing the prepared final liquid medicine 1-13 at 25 ℃, sampling at 0 hour, 2 hours, 4 hours, 6 hours and 8 hours respectively, and detecting the isomer change condition.

Detection result of isomer after compatibility of liquid medicine

From the above detection results, it can be seen that: the injection solvent is a main factor influencing the isomer change of the final compatible liquid medicine of the temsirolimus injection, and the injection solvent provided by the invention can obviously reduce the trend of isomer increase in the clinical use process of the temsirolimus injection, and provides a product with better clinical curative effect for the temsirolimus injection.

Claims (6)

1. A solvent for temsirolimus injection is characterized by comprising a solubilizer, L-arginine, methylparaben and water for injection; wherein the solubilizer is selected from one or more of tween 80, tween 20 and tween 40; the mass volume ratio concentration range of the solubilizer is 7.5 to 12.5 percent, the mass volume ratio concentration range of the L-arginine is 1.0 to 1.6 percent, and the mass volume ratio concentration range of the methylparaben is 5 to 10 percent.

2. The solvent for injection of temsirolimus injection as claimed in claim 1, wherein the solubilizer is tween 80.

3. The temsirolimus injection solvent of claim 1, wherein the mass-to-volume concentration of the solubilizer is in the range of 10%.

4. The temsirolimus injection solvent of claim 1, wherein the concentration of L-arginine ranges from 1.4% by mass/volume.

5. The temsirolimus injection solvent of claim 1, wherein the mass-to-volume concentration of methylparaben is in the range of 7.5%.

6. A method for preparing a temsirolimus injection solvent of claim 1, comprising the steps of:

weighing a prescription amount of solubilizer and methyl paraben, adding the solubilizer and the methyl paraben into a proper amount of water for injection, stirring for dissolving, weighing a prescription amount of L-arginine, adding the L-arginine into the solution, metering the volume to the full volume with the water for injection, and stirring uniformly; filtering, bottling, visually inspecting, and packaging to obtain the final product.